To investigate a potential mechanism linking hyperinsulinemia with hypertension and atherosclerosis, we examined whether insulin modulates the vasoactive effects of endothelin (ET-1), a vasoconstrictor and mitogenic peptide. To this purpose, we measured the forearm blood flow (FBF; strain-gauge plethysmography) responses to ET-1 receptor blockade during infusion of either saline or insulin in 8 healthy subjects on 2 separate days. During saline, intraarterial infusion of an ET/A-receptor blocker (BQ-123, 100 nmol/min for 60 min), alone and in combination with an ET/B-receptor antagonist (BQ-788; 50 nmol/min for further 60 min) did not significantly change FBF (2.9+/-0.2 [mean+/-SEM] mL/min/dL before, 2.9+/-0.2 mL/min/dL after BQ-123 alone, 2.8+/-0.2 mL/min/dL after the combination of BQ-123 and BQ-788; P=0.29). Insulin administration (0.1 mU/kg/min for 2 hr) resulted in a marked increase in local insulin concentration (from 3+/-1 to 295+/-69 microU/mL; P=0.004), but did not modify FBF (2.3[unreadable]0.1 mL/min/dL before and 2.2+/-0.1 mL/min/dL after 2 hr of insulin infusion; P=0.58). During hyperinsulinemia, ET-1 receptor antagonism caused a vasodilator effect, with a FBF increase of 25+/-9% after 60 min of selective ET/A blockade and of 52+/-7% after 60 min of combined ET/A and ET/B antagonism (P<0.001). These findings suggest that insulin stimulates vascular production of ET-1, which may contribute to the hypertensive and atherogenic effects of hyperinsulinemia. The observation that insulin does not modify vascular tone in the absence of ET-1 receptor blockade is compatible with the concurrent activation of vasodilator mechanisms that physiologically balance the vasoconstrictor effect of increased ET-1.